What question did this study set out to answer?

The aim is to explore how the loss of GPx2 affects breast cancer metastasis through redox regulation and metabolic changes.

April 5, 2026

Abstract 848: Redox regulation of breast cancer metastasis via phenotypic and metabolic adaptation.

Key Points

The aim is to explore how the loss of GPx2 affects breast cancer metastasis through redox regulation and metabolic changes.
Utilized PyMT mouse model with GPx2 knockout.
Analyzed tumor characteristics using flow cytometry and metabolic profiling.
Measured reactive oxygen species and HIF1α stabilization in tumors.
Observed increased lung metastasis and hybrid EMT cell populations in GPx2-deficient tumors.
Metabolic profiling showed fatty acid oxidation as the primary energy source.
Noted a shift to glycolytic metabolism in lung metastases derived from GPx2-KO tumors.

Abstract

Abstract Background: Tumor heterogeneity fuels breast cancer metastasis by selecting subpopulations withepithelial-mesenchymal (EMT) plasticity and stemness. Loss of the antioxidant enzyme glutathione peroxidase 2 (GPx2) in the PyMT mouse model promotes phenotypic and metabolic reprogramming through ΔNp63-regulated hybrid EMT and fatty acidoxidation (FAO)-driven metabolism. Results: Using our newly engineered PyMT/GPx2 knockout (KO) transgenic mouse model, we observed a striking increase in reactive oxygen species (ROS), HIF1α stabilization, vascular malformation, proliferation (Ki67), stemness (organoid formation), and lung metastasis compared with control tumors. GPx2-deficient tumors were markedly enrichedfor hybrid EMT cells co-expressing p63, KRT8, and KRT14. Flow cytometry confirmed that ∼85% of GPx2-KO tumor cells were hybrid (CD104+/CD44+), with only minor epithelial (CD104+/CD44-, ∼4%) and mesenchymal (CD104-/CD44+, ∼0.8%) fractions. Metabolic profiling revealed FAO as the dominant energy source in GPx2-KO tumors, supported by Seahorse assays showing elevated mitochondrial ATP production, a higherOCR/ECAR ratio, and enhanced palmitate oxidation. GPx2 loss increased p-AMPK,indicative of AMPK-mediated OXPHOS activation, and upregulated GLUT1 whilesuppressing de novo lipogenesis. These changes indicate dependence on exogenousfatty acids through CD36/CPT1-mediated β-oxidation. Notably, lung metastases derivedfrom GPx2-KO tumors showed a shift toward glycolytic metabolism, highlightingmetabolic plasticity during dissemination. Conclusion: GPx2 loss integrates redox dysregulation with EMT and metabolic reprogramming, fostering hybrid E/M cells endowed with high metastatic potential and adaptive energymetabolism. Clinical implications: Targeting ΔNp63 signaling or FAO pathways may selectively eliminate metabolically flexible, aggressive hybrid tumor populations, offering a potential strategy to mitigate breast cancer metastasis. Citation Format: Rachel Hazan, Viney Kumar, Outhiriaradjou Benard, Larry premprashant chaudhary, mahaldeep kaur, Ian, Bethesda, Norton. Redox regulation of breast cancer metastasis via phenotypic and metabolic adaptation abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 848.

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